Over the past year we have pursued studies on B lymphocyte immunopathogenesis in HIV disease by focusing on 1) the genotypic, phenotypic and functional correlates of B cell dysfunction in the setting of ongoing viral replication, 2) antigen-specific B cell effector and memory responses in HIV-infected patients, and 3) mechanisms of HIV virion trapping in lymph nodes. The first project on the genotypic, phenotypic and functional aspects of B cell dysfunction in HIV disease was completed. We used DNA microarrays to establish the profile of genes that were dysregulated in B cells of HIV-viremic patients compared to HIV-aviremic and HIV-negative individuals. Over 40 genes were found to be upregulated in HIV-viremic patients, of which over 75% belonged to one of two categories, interferon induction or B cell terminal differentiation. The pattern of genes found to be upregulated in HIV-viremic patients clearly suggests that HIV induces immune activation that leads to aberrant gene activation that ultimately translates into increased propensity to B cell death through apoptosis. By combining phenotypic and functional assays to validate the microarray data we were able to demonstrate that ongoing HIV replication leads to increased expression of the death receptor Fas and decreased expression of the B cell survival receptor Baff-R with a combined effect of increased cell death in response to respective ligand-receptor interactions. The second project undertaken in 2004 was a large clinical study aimed at evaluating the B cell response of HIV-infected patients to influenza vaccination. We compared their influenza-specific effector and memory B cell responses, as well as antibody titers to those of HIV-negative healthy donors. We found that all HIV-infected patients had lower B cell memory responses compared to HIV-negative individuals and that the effector and antibody responses were also lower in the patients with low CD4+ T cell counts and high HIV viral burden. All parameters of the anti-influenza B cell responses were found to correlate to CD4+ T cell count and to a lesser degree, HIV plasma viremia. Finally, we have continued to investigate HIV trapping to lymph nodes in a mouse model and over the past year we have conclusively established using knockout mice and ligand-displacing antibody treatments that the complement receptor 2 or CD21 is essential for virion trapping. Future studies will evaluate the possibility of using the HIV-displacing antibodies to reduce HIV burden in vivo.